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Disease/Disorder

Definition

Injury to the brain and central nervous system can lead to multiple challenging sequelae. Effects on behavior, in the form of conditions such as agitation, aggression, and apathy, can be especially difficult. These conditions can be indicators of pathology and can also themselves have negative consequences. Whether considered as a continuum or separate entities, these clinical problems warrant careful evaluation and treatment.

Agitation is a subtype of delirium, characterized by an excess of behaviors including aggression, akathisia, disinhibition, and emotional lability. Agitation includes a spectrum of behaviors ranging from verbal threats and motor restlessness; to harmful, aggressive, and destructive behaviors.1

Aggression, a complex behavior comprised of sensory, emotional, cognitive, and motor elements, can include behaviors that are damaging to individuals or property; attitudes, moods, or gestures that people find threatening or intimidating; or purposeful behavior that is disruptive to social integration. Aggression includes verbal aggression, physical aggression toward others, objects, or self. Verbal aggression is most common.1,2

Apathy, generally speaking, is a decrease in or lack of motivation. It is also described as a decrease in self-generated, voluntary, goal-directed, and purposeful behaviors.3,4

Etiology

Agitation and aggression can occur within the context of any condition that affects the brain. Such conditions include traumatic brain injury (TBI), non-traumatic brain injury (including ischemic and thrombotic stroke), hypoxic-ischemic brain injury, neuro-degenerative disorders, neoplastic disorders, central nervous system infection, and toxic or metabolic encephalopathy.1

Apathy is seen in multiple psychiatric conditions (including depression and schizophrenia) as well as neurologic disorders (such as Alzheimer’s and other types of dementia), in addition to Parkinson ’s disease, stroke, traumatic brain injury, cerebral infections, and tumors.3,4

Secondary conditions that commonly occur with TBI and stroke can present with agitation, aggression, or apathy. For example, a person with severe aphasia may become frustrated and then exhibit behavioral symptoms. An individual recovering from brain injury may exhibit similar symptoms in the setting of physiologic derangements like infections or pain.

Delirium is a form of generalized brain failure that can occur with or without brain injury. Contributing factors include medications, sleepy wake cycle abnormalities, effects of acute illness, or some combination. It is common for individuals with delirium to present with agitation. Agitation after brain injury may be a type of delirium but may require distinct interventions.

Epidemiology including risk factors and primary prevention

Agitation has been estimated to occur in 40-70% of people with TBI and at least 35% of patients in acute rehabilitation units after TBI.5

The incidence and prevalence of agitation can be dependent on the underlying etiology. Patients are more likely to have agitation after head injury if they are still in the state of post-traumatic amnesia, if their injury was more severe, if they have a premorbid history of substance abuse,infection, impaired cognition or lower functional status.1,6 Agitation has been noted in 20 to 45% of patients with mild cognitive impairment and up to 90% of patients with advanced dementia.7

Estimates about the epidemiology of aggression also vary with underlying cause. Among patients with severe TBI, the prevalence of aggression is generally considered to be approximately 25-30%. Patients are more likely to have aggression after TBI if they have:

  • a pre-injury history of mood disorder, alcohol or substance abuse
  • impaired social function
  • frontal lobe lesion
  • prior episodes of head injuries

Other risk factors for aggression include:

  • the presence of delirium
  • longer period of post-traumatic amnesia
  • low cognitive status
  • comorbid medical complications
  • impaired language function.8,9

Aggression is more common during the acute period following head trauma and in patients with other neurobehavioral symptoms, such as impulsivity, disinhibition, and sleep issues, than in patients without neurobehavioral symptoms.9 In dementia, the prevalence of aggression has been estimated to range from 20 to 40%. People with dementia who demonstrate aggressive behaviors also tend to have other neuropsychiatric symptoms. Aggression in dementia has also been correlated with disease severity, depression, and degree of cognitive impairment.7

The reported incidence of apathy varies with the etiology. It has been noted to occur in more than 20% of TBI survivors. Apathy has been noted to occur in about one third of post-stroke patientsand more than half of patients who have Alzheimer’s disease.3,4

Patho-anatomy/physiology

The pathology underlying agitation and aggression is not fully understood and is likely multifactorial. Contributing cerebral structural and chemical abnormalities include damage to the frontal and temporal lobes, injury to the prefrontal cortex or orbitofrontal cortex injury to the thalamus and limbic system, and impaired regulation of serotonin, norepinephrine, and dopamine.5,10

It is postulated that dysfunction in the balance between areas of the brain involved in aggressive behavior (amygdala and insula) and those involved in inhibiting aggression (prefrontal/ orbitofrontal cortex) can influence behavior. Furthermore, violent behavior has been associated with abnormal neuro-electrical activity involving the amygdala region.11

Apathy has been associated with damage to multiple areas of the brain, including the frontal lobe, basal ganglia, and cingulate gyrus. Blockade of dopamine pathways also appear to play a role.3,4

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

Agitation, aggression, and apathy are often sequela of various diseases and injuries, so improvement can be seen with recovery of the underlying etiology. In progressive conditions, ongoing and potentially worsening agitation, aggression, and apathy can occur.

Agitation following TBI tends to resolve when the delirium resolves. In progressive neurodegenerative disorders, including dementia, agitation may be an ongoing problem.

Aggression following TBI can either resolve when the agitation resolves or remain an ongoing problem. In progressive neurodegenerative disorders, including dementia, aggression may persist.

Apathy may improve if the underlying condition resolves or is adequately treated.

Specific secondary or associated conditions and complications

Agitation and aggression can have deleterious sequelae for patients with TBI and other acquired brain injuries. Agitation and aggression have been associated with interruptions and disruptions of care. These behavioral changes have also been correlated with increased lengths of stay in both hospital and acute rehabilitation settings. These patients pose a special challenge for traditional brain injury rehabilitation units, which are generally unlocked and also care for other vulnerable patients. Aggression, then, can be a barrier to admission to acute rehabilitation and to success in acute rehabilitation programs.8 The overall cost of care can be increased. There is also a high potential for injury to the patient or others. The burden on caregivers can be more intense when a patient is agitated or aggressive. Agitation and aggression can also lead to significant social issues, including alienation from family and loss of employment. Further, there can be difficult legal issues, which can be exaggerated if the patient engages in criminal activity.10

Essentials of Assessment

History

For patients with agitation and aggression, a detailed history should include the history of the inciting injury or disease, description of agitation/aggressive behavior (from patient, observer, family, or caregivers), psychosocial history (including pre-injury behavioral traits, education, employment, substance abuse), medical history (including neurological, psychiatric and endocrine systems), sleep history, nutritional status, and pain assessment. Bowel and bladder changes, including constipation, urinary retention, and incontinence, require thorough investigation because they may indicate infection or other serious pathology. It is important to review all medications including recent additions, discontinuations, or changes. History of substance abuse, including drugs, tobacco, and alcohol use, are important as withdrawal, craving, and other sequela of use could contribute to the patient’s agitation and aggression.5

Efforts should be made to communicate directly with the patient to elicit relevant information. This is important to not only better understand their history but may also reduce patient’s frustrations that they are not being included in their care. Techniques such as the utilization of yes/no questions may be indicated in the setting of aphasia or other communication barriers.

For patients with apathy, the history should include past medical history (including history of psychiatric illness), personality changes, and progression of disease. To rule out a potentially treatable cause of apathy, screening for depression should be completed.3

Physical examination

For agitation and aggression, the physical exam should include vital signs (may be abnormal in cases of infection or medical instability), neurological examination (could provide focal findings or clues to the underlying pathology), cardiovascular and pulmonary evaluations (acute medical issues), and musculoskeletal examination (potential sources of discomfort or pain). Assessment of overall level of cognition, alertness, insight, aphasia, hallucinations, memory deficits, and other issues may yield clues about agitation and aggression.10

Functional assessment

Patients with agitation and aggression require careful functional assessments. Agitation and aggression are associated with abnormalities in executive function, impulse regulation, and impaired ability to perform basic self-care tasks. Further, the behaviors associated with agitation and aggression can interfere with caregiving activities in patients who would benefit from assistance. The negative effect on ability to function can be profound. Ranchos Los Amigos scale may be helpful in categorizing TBI patient’s recovery and for communicating their status with other team members.2,8

For apathy, the patient’s affect as well as what they do from a functional standpoint should be assessed. It is important to differentiate whether patients are not doing activities of daily living (ADLs)/self-care because they are not motivated, or not being aware of need to do those tasks in the setting of cognitive impairment or lack of insight.3

Laboratory studies

For agitation and aggression, the basic laboratory work-up would start with chemistry and complete blood count to evaluate for common metabolic, electrolyte, and/or hematologic derangements that might be contributing to behavior. A urinalysis and urine culture can provide information about potential bladder and urinary dysfunction. Other tests may be required to evaluate for specific metabolic problems and infectious issues. Cerebrospinal fluid analysis may be warranted, particularly if the underlying cause of the agitation or aggression is thought to be infectious, inflammatory, or related to a paraneoplastic syndrome affecting the central nervous system.12

Imaging

For patients with agitation and aggression, brain imaging such as CT or MRI would be needed to ascertain an underlying etiology if it were not already known. If the agitation or aggression is possibly due to pain, x-rays can evaluate for previously undiagnosed fractures or heterotopic ossification. Abdominal imaging, including x-rays or CT scan, can help evaluate potential bowel issues, including constipation, ileus, and other gastrointestinal abnormalities.5

Supplemental assessment tools

Agitation: For patients with TBI, the Agitated Behavior Scale can help clinicians quantify the agitated behaviors at a certain point in time and over a period of time.13 For patients with dementia, the Pittsburgh Agitation Scale or Behavioral Pathology in Alzheimer’s Disease Rating Scale may be helpful.14 A sleep log might also be beneficial to help determine if inadequate sleep is contributing.1

Aggression: Commonly used tools include the Neurobehavioral Functioning Inventory, Neuropsychiatric Inventory, Neurobehavioral Rating Scale, and the Overt Aggression Scale-Modified for Neurorehabilitation.2

Apathy: There are multiple available assessment tools, including the Apathy Evaluation Scale, the Apathy Scale, and the Apathy Inventory. Furthermore, the Neuropsychiatric Inventory and the Unified Parkinson’s Disease Rating Scale both assess apathy as part of their overall measure.3,15

Frontal seizures can be mistaken as behavioral issues. In some cases, an electroencephalogram (EEG) may, therefore, be indicated.

Environmental

Agitation and aggression can be impacted both positively and negatively by environmental issues. These include the amount of stimulation, light and noise levels, space and privacy issues, and interactions with staff members, other patients, and family/friends. Environmental interventions are crucial components of management.12,16,17

Rehabilitation Management and Treatments

At different disease stages

For agitation and aggression, interventions should be the least restrictive possible. Safety of the patient, family, staff, and others is a primary consideration. Initial management includes evaluation and treatment of possible underlying causes, environmental modifications (reduction of stimuli including televisions and phones, visitors, other patients, and medical equipment), normalizing the sleep-wake cycles, optimizing nutrition and hydration status, and addressing pain. Physical restraints are avoided whenever possible. Specialty enclosed beds, such as net beds, can be very helpful in some circumstances. Clinicians need to monitor patients carefully in the rare instances where restraints or net beds are required.12,16

Pharmacological treatment is commonly required as an additional measure. Unfortunately, there is not definitive data supporting a certain medication or regimen. In acute TBI, the most supported medications are the beta- blockers propranolol and pindolol. Antiepileptics with mood regulatory effects, such as carbamazepine and valproate, are other considerations. Atypical antipsychotics such as olanzapine can also help symptoms. Neuroleptics, antidepressants, benzodiazepines, and buspirone are considered second-line treatments. Analgesics can be efficacious if pain is contributing to behavioral symptoms. Analgesics can also have beneficial anxiolytic and sedating effects. Medications geared toward treating potential neuropathic pain, such as gabapentin, or spasticity, such as baclofen and tizanidine, can be helpful as well. Typical antipsychotics, most notably haloperidol, should be avoided if at all possible, because these medications may impede cognitive recovery.5,12,18

For chronic TBI patients with irritability and aggression not accompanied by anger, amantadine may provide some benefit.19 Other medications that can be trialed for chronic aggression in the brain injury population include beta blockers, methylphenidate, and valproic acid. Other antiepileptics, such as oxcarbazepine and carbamazepine, can be considered but are not supported by controlled studies.5

Cognitive behavioral therapy has demonstrated benefits for aggression. Interventions, including group and individual therapies focused on anger education and self-monitoring, likely help by optimizing self-awareness and also by helping patients track, check, and reduce their aggressive comments and other behaviors.1,8

There are no FDA-approved medication treatments for apathy. Some small studies and case reports have demonstrated possible beneficial effects of certain medications. These include anti-cholinesterase inhibitors such as rivastigmine, donepezil, and galantamine and psychostimulants such as methylphenidate, modafinil and armodafinil. Antidepressants, especially more activating ones, are also used in this population, but need to be used with caution because they can worsen apathy in some patients.3

Coordination of care

The interdisciplinary treatment team includes the physician, nurse, occupational therapist, physical therapist, recreation therapist, speech and language pathologist, neuropsychologist and others. Care can be provided in a variety of settings, including inpatient rehabilitation units, outpatient therapies, structured day programs, residential treatment, inpatient psychiatric treatment, and in-home cognitive services.12

Cognitive rehabilitation can be a particularly important part of functional recovery when agitation, aggression, or apathy occur. An international panel of experts in cognitive rehabilitation after TBI (INCOG) has developed guidelines for patients with moderate to severe TBI who have cleared post-traumatic amnesia but have ongoing cognitive sequelae. These guidelines can provide a framework for clinicians who are planning, providing, and evaluating therapies to affected individuals.20

Patient & family education

In cases of acute brain injury, where the agitation or aggression may be transient and is consistent with stages of recovery, family members need education about the situation. Visitors are also part of the therapeutic environment, so their visits may need to be shortened or scheduled around rest periods for the patient. Families should have knowledge of potential situations that trigger agitated or aggressive behaviors so these can be avoided. In cases of neurodegenerative injury, including dementia, families need education about the expected prognosis and time course. They may need assistance setting up ongoing care for the patient.16

Cutting Edge/Emerging and Unique Concepts and Practice

For agitation and aggression, there have been reports of the successful use of electroconvulsive therapy in patients whose agitation seems refractory to medications and environmental modifications. There is not yet sufficient evidence to recommend it, and there may be effects, including cognitive slowing, that can be negative in this population.17

Complementary and alternative therapy modalities, including massage therapy and essential oils, have also been implemented with some success. Music therapy, including exposing patients to music they liked before the injury, also may be beneficial.21 Rehabilitation therapies, such as physical therapy interventions like mobilization, may be helpful to decrease agitation and facilitate subsequent progress in rehabilitation.22

In a small study, neuromodulation with repetitive transcranial magnetic stimulation demonstrated possible benefit as a treatment modality for apathy in patients with Alzheimer’s disease.23 More research is needed to determine if neuromodulation is beneficial in other disease processes that result in apathy.

Providing care via telehealth or other virtual means can be helpful for people with brain injuries and their families. As technology becomes available, patients and clinicians become more comfortable using it, and other logistics and barriers (such insurance, licensure) are addressed, this newer way of delivering care may become even more common. Neuropsychiatric sequelae, including aggression, can be assessed. Cognitive behavior therapy and related interventions, along with family education, can be provided. This may help people with chronic effects of brain injury, who may have difficulty coming in to the clinic regularly, access essential and beneficial care.24

Gaps in the Evidence-Based Knowledge

For aggression and agitation following traumatic and acquired brain injury, there are many unsettled questions for rehabilitation clinicians and investigators to consider. It is possible that future therapies could shorten the length of the agitated and aggressive period of recovery, thereby lessening the burden of these conditions. This clinical area would benefit from studies utilizing consistent nosology and methodology to facilitate generalizability. Better evidence about the potential use of medications is also needed.25

References

  1. Wortzel, HA, Silver JM. Behavioral dyscontrol. In Silver JM, McAllister TW, Archinieagas DB. Textbook of Traumatic Brain Injury, 3rd Ed. 2019. American Psychiatric Association Publishing: Washington DC.
  2. Whitwam S, Jones KA. Assessing aggression following acquired brain injury: A systematic review of assessment measures. 2019; 33: 1491-1502.
  3. Starkstein SE, Pahissa J. Disorders of diminished motivation. In Silver JM, McAllister TW, Archinieagas DB. Textbook of Traumatic Brain Injury, 3rd Ed. 2019. American Psychiatric Association Publishing: Washington DC.
  4. Worthington A, Wood RLL. Apathy following traumatic brain injury: A review. Neuropscychologia 2018l 118: 40-47.
  5. Rahmani E, Lemelle TM, Samarbafzadeh et al. Pharmacological treatment of agitation and/ or aggression in patients with traumatic brain injury: A systematic review of reviews. J Head Trauma Rehabil. 2021: E262-E283.
  6. Bogner J, Barrett RS, Hammond FM et al. Predictors of agitated behavior during inpatient rehabilitation for traumatic brain injury. Arch Phys Med Rehabil 2015; 96 (8 Suppl 3): S274-281.
  7. Wolf MU, Goldberg Y, Freedman M. Aggression and agitation in dementia. Am Acad Neurol Continuum Journal. 2018; 783-803.
  8. Iruthayarajah J, Alibrahim F, Mehta S, et al. Cognitive behavioral therapy for aggression among individuals with moderate to severe acquired brain injury: A systematic review and meta-analysis. Brain Inj 2018; 32(12), 1443-1449.
  9. Roy D, Vaishnavi S, Han D, Rao V. Correlates and prevalence of aggression at six months and one year after first-time traumatic brain injury. J Neuropsychiatry Clin Neurosci. 2017; 29: 334-342.
  10. Wortzel HS, Brenner LA. Neuropsychiatric symptoms and syndromes. In Zasler ND, Katz DI, Zafonte RD. Brain Injury Medicine, 3rd Ed. 2022. Springer: New York.
  11. Epstein D.J., Legarreta M., Bueler E., King J., McGlade E., Yurgelun-Todd D. Orbitofrontal cortical thinning and aggression in mild traumatic brain injury patients. Brain Behav. 2016;6:e00581. doi: 10.1002/brb3.581. 
  12. Laute H, Plantier D, Wiart L, et al. Care management of the agitation or aggressiveness crisis in patients with TBI: Systematic review of the literature and practice recommendations. Ann Phys Rehabil Med 2016; 59: 58-67.
  13. Corrigan JD. Development of a scale for assessment of agitation following traumatic brain injury. J Clin Exp Neuropsychol. 1989;11:261-267.
  14. Rosen J, Burgio L, Kollar M, et al. The Pittsburgh Agitation scale: A user-friendly instrument for rating agitation in dementia patients. Am J Geriatr Psychiatry 1994; 2: 52-59.
  15. Berman K, Brodaty H, Withall A, Seeher K. Pharmacologic treatment of apathy in dementia. Am J Geriatr Psychiatry. 2012;20:104-122.
  16. Carrier SL, Ponsford J, McKay A. Family experiences of supporting a relative with agitation during early recovery after traumatic brain injury. Neuropsychol Rehabil 2023; DOI: 10.1080/09602011.2023.2219061.
  17. Carrier SL, Ponsford J, Phyland RK et al. Effectiveness of non-pharmacological interventions for agitation during post-traumatic amnesia following traumatic brain injury: A systematic review. Neuropsychol Rev 2023; 33: 374-392.
  18. McKay A, Trevena-Peters J, Ponsford J. et al. The use of atypical antipsychotics for managing agitation after traumatic brain injury. J Head Trauma Rehabil 2020; 36: 149-155.
  19. Hammond FM, Malec JM, Zafonte RD, et al. Potential impact of amantadine on aggression in chronic traumatic brain injury. J Head Trauma Rehabil. 2017; 32: 302-318.
  20. Bayley MT, Tate R, Douglas JM, et al. INCOG guidelines for cognitive rehabilitation following traumatic brain injury: Methods and overview. J Head Trauma Rehabil. 2014; 29: 290-306.
  21. Park S, Williams RA, Lee D. Effect of preferred music on agitation in traumatic brain injury. West J Nurs Res 2016; 38: 394-410.
  22. Spiteri C, Williams G, Kahn M, et al. Factors associated with physical therapy engagement during the period of posttraumatic amnesia. JNPT 2022; 46: 41-48.
  23. Padala PR, Boozer EM, Lensing SY, et al. Neuromodulation for apathy in Alzheimer’s Disease: A double-blind, randomized, sham-controlled pilot study. J. Alzheimer’s Disease. 2020; 77:1483-1493
  24. McDonald S, Trimmer E, Newby J, Grant S, Gertler P, Simpson-Grahame K. Providing on-line support to families of people with brain injury and challenging behavior: A feasibility study. Neuropsychol Rehabil. 2021; 31: 392-413. 25.Carrier SL, Hicks AJ, Ponsford J, et al. Managing agitation during early recovery in adults with traumatic brain injury: An international survey Ann Phys Rehabil Med 2021. 64: 101532.

Original Version of the Topic

Joseph A. Rosenthal, MD. Agitation/aggression/apathy after brain injury and other CNS disorders. 9/20/2013.

Previous Revision(s) of the Topic

Joseph A. Rosenthal, MD, Diane Mortimer, MD. Agitation/aggression/apathy after brain injury and other CNS disorders. 8/19/2016.

Joseph A. Rosenthal, MD, Diane Mortimer, MD, Karen Woods, MD. Agitation/aggression/apathy after brain injury and other CNS disorders. 5/24/2021

Author Disclosures

Diane Schretzman Mortimer, MD
Nothing to Disclose

Emily Hines, MD
Nothing to Disclose